The proposed study further investigates diminished sensory gating in schizophrenia. The diminished ability to gate or filter repetitive stimuli is demonstrated by a conditioning-testing paradigm using the P50 auditory evoked potential. Trains of paired clicks are presented. Normals show a decremented response to the second click, which is evidence for the action of a sensory gating mechanism. Schizophrenics, by not decrementing the second response, show failure of this mechanism. Diminished gating is not significantly altered in schizophrenics on neuroleptics, although the initial amplitude and latency of the P50 wave are normalized. Manics also show diminished gating, but it normalizes when they become euthymic. In the present grant period we showed that diminished gating is a familial trait in schizophrenia which is generally present in one parent and half the siblings, in addition to the schizophrenic patient. In a unique experimental brain graft treatment for Parkinson's disease, it is induced by an increase in central dopaminergic activity. It is present in many nonschizophrenic psychiatric in-patients, but only during acute illness. Normal sensory gating develops gradually in adolescence. We developed an animal model in rats in which a similar potential is recorded from the CA3 region of hippocampus. We propose in the next grant period to combine sensory gating measurements with other biological measurements in which abnormalities have been proposed as risk factors for schizophrenia: smooth pursuit eye movements, brain structure, and catecholamine metabolites. By comparing schizophrenics with their siblings, we will attempt to determine which factors are necessary and sufficient to produce schizophrenia. We will continue to study the effects of changes in catecholamine activity on auditory-evoked potentials in schizophrenics, as well as in nonschizophrenic psychiatric in-patients and normals. We will compare the development of sensory gating in normal children and children of schizophrenic mothers. Finally, we will use our animal model to attempt to specify at the single neuron level the neurobiology of normal and abnormal sensory gating.